Dextropropoxyphene


Dextropropoxyphene is an analgesic in the opioid category, patented in 1955 and manufactured by Eli Lilly and Company. It is an optical isomer of levopropoxyphene. It is intended to treat mild pain and also has antitussive and local anaesthetic effects. The drug has been taken off the market in Europe and the United States due to concerns of fatal overdoses and heart arrhythmias. It is still available in Australia, albeit with restrictions after an application by its manufacturer to review its proposed banning. Its onset of analgesia is said to be 20–30 minutes and peak effects are seen about 1.5–2.0 hours after oral administration.
Dextropropoxyphene is sometimes combined with acetaminophen. Trade names include Darvocet-N, Di-Gesic, and Darvon with APAP. The British approved name of the paracetamol/dextropropoxyphene preparation is co-proxamol ; however, it has been withdrawn since 2007, and is no longer available to new patients, with exceptions. The paracetamol combination are known as Capadex or Di-Gesic in Australia, Lentogesic in South Africa, and Di-Antalvic in France.
Dextropropoxyphene is known under several synonyms, including:
  • Alpha-d-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol propionate
  • propanoate
  • -1,2-Diphenyl-2-propionoxy- 3-methyl-4-di-methylaminobutane
  • Desoxypropiophen

    Uses

Analgesia

Dextropropoxyphene is generally considered a weak analgesic, with several studies finding its efficacy is no better than acetaminophen.
Like codeine, it is a weak opioid. However, dextropropoxyphene has one-third to one-half of the analgesic activity of codeine.

Restless legs syndrome

Dextropropoxyphene has been found to be helpful in relieving the symptoms of restless legs syndrome.

Contraindications

Dextropropoxyphene is contraindicated in patients allergic to paracetamol or dextropropoxyphene, and in alcoholics. It is not intended for use in patients who are prone to suicide, anxiety, panic, or addiction.

Side effects

Severe toxicity can occur with small increments above the therapeutic dose including cardiotoxicity, and fatal overdoses. This is especially true when the drug is combined with alcohol.
Other side effects include:
  • Constipation
  • Itching
  • Drowsiness
  • Nausea
  • Sensorineural deafness
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Pharmacology

Dextropropoxyphene acts as a mu-opioid receptor agonist. It also acts as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist, as well as a weak serotonin reuptake inhibitor.

Toxicity

Overdose is commonly broken into two categories - liver toxicity and dextropropoxyphene overdose. It may also account for mood- or thought-altering effects.
An overdose of dextropropoxyphene may lead to various systemic effects. Excessive opioid receptor stimulation is responsible for the CNS depression, respiratory depression, aspiration pneumonia, miosis, and gastrointestinal effects seen in propoxyphene poisoning. In the presence of amphetamine, propoxyphene overdose increases CNS stimulation and may cause fatal convulsive seizures.
In addition, both propoxyphene and its metabolite norpropoxyphene have local anesthetic effects at concentrations about 10 times those necessary for opioid effects. Norpropoxyphene is a more potent local anesthetic than propoxyphene, and they are both more potent than lidocaine. Local anesthetic activity appears to be responsible for the arrhythmias and cardiovascular depression seen in propoxyphene poisoning.
Both propoxyphene and norpropoxyphene are potent blockers of cardiac membrane sodium channels, and are more potent than lidocaine, quinidine, and procainamide in this respect. As a result, propoxyphene and norpropoxyphene appear to have the characteristics of a Vaughn-Williams Class Ic antiarrhythmic.
These direct cardiac effects include decreased heart rate, decreased contractility, and decreased electrical conductivity. These effects appear to be due to their local anesthetic activity and are not reversed by naloxone. Widening of the QRS complex appears to be a result of a quinidine-like effect of propoxyphene, and sodium bicarbonate therapy appears to have a positive direct effect on the QRS dysrhythmia.
Seizures may result from either opioid or local anesthetic effects. Pulmonary edema may result from direct pulmonary toxicity, neurogenic/anoxic effects, or cardiovascular depression.
Balance disorder is possible, with risk of falls from standing height.

Available forms

Propoxyphene was initially introduced as propoxyphene hydrochloride. Shortly before the patent on propoxyphene expired, propoxyphene napsylate form was introduced to the market. The napsylate salt is claimed to be less prone to non-medical use, because it is almost insoluble in water, so cannot be used for injection. Napsylate also gives lower peak blood level. Because of different molar mass, a dose of 100 mg of propoxyphene napsylate is required to supply an amount of propoxyphene equivalent to that present in 65 mg of propoxyphene hydrochloride.
Before the FDA-directed recall, dextropropoxyphene HCl was available in the United States as a prescription formulation combined with paracetamol in ratio from 30 mg / 600 mg to 100 mg / 650 mg, respectively, usually named Darvocet.
In Australia, dextropropoxyphene is available on prescription, both as a combined product known as Doloxene, however its use has been restricted.

Drug testing

Detectable levels of propoxyphene/dextropropoxyphene may stay in a person's system for up to 9 days after last dose and can be tested for specifically in nonstandard urinalysis, but may remain in the body longer in minuscule amounts. Propoxyphene does not show up on standard opiate/opioid tests because it is not chemically related to opiates as part of the OPI or OPI 2000 panels, which detect morphine and related compounds. It is most closely related to methadone.

History

Dextropropoxyphene was successfully tested in 1954 as part of US Navy and CIA-funded research on nonaddictive substitutes for codeine.

Use in organic synthesis

Without the propionyl group on the oxygen, the non-esterified alcohol precursor of propoxyphene have been employed as stoichiometric chiral reagents for asymmetric carbonyl reduction reactions involving aluminium hydride reagents.

Usage controversy and regulation

Dextropropoxyphene is subject to some controversy; while many physicians prescribe it for a wide range of mildly to moderately painful symptoms, as well as for treatment of diarrhea, many others refuse to prescribe it, citing limited effectiveness. In addition, the therapeutic index of dextroproxyphene is relatively narrow.
Caution should be used when administering dextropropoxyphene, particularly with children and the elderly and with patients who may be pregnant or breastfeeding; other reported problems include kidney, liver, or respiratory disorders, and prolonged use. Attention should be paid to concomitant use with tranquillizers, antidepressants, or excess alcohol.
Darvon, a dextropropoxyphene formulation made by Eli Lilly, which had been on the market for 25 years, came under scrutiny in 1978 by consumer groups that said it was associated with suicide. Darvon was never withdrawn from the market, until recently, but Lilly has waged a sweeping, and largely successful, campaign among doctors, pharmacists, and Darvon users to defend the drug as safe when it is used in proper doses and not mixed with alcohol. After determining the risks outweigh the benefits, the USFDA requested physicians stop prescribing the drug. On November 19, 2010, the FDA announced that Xanodyne Pharmaceuticals agreed to withdraw Darvon and Darvocet in the United States, followed by manufacturers of dextropropoxyphene.

Australia

In Australia, both pure dextropropoxyphene capsules, marketed as Doloxene, and combination tablets and capsules all containing 32.5 mg dextropropoxyphene HCl with 325 mg paracetamol, which are currently available on prescription were supposed to be withdrawn from 1 March 2012, but Aspen Pharma sought a review in the Administrative Appeals Tribunal which ruled in 2013 that the drugs could be sold under strict conditions.

Canada

On December 1, 2010, Health Canada and Paladin Labs Inc. announced the voluntary recall and withdrawal of Darvon-N from the Canadian market and the discontinuation of sale of Darvon-N.

European Union

In November 2007, the European Commission requested the European Medicines Agency to review the safety and effectiveness of dextropropoxyphene based medicines and on 25 June 2009 the EMA recommended a gradual withdrawal throughout the European Union. The EMA's conclusion was based on evidence that dextropropoxyphene-containing medicines were weak painkillers, the combination of dextropropoxyphene and paracetamol was no more effective than paracetamol on its own, and the difference between the dose needed for treatment and a harmful dose was too small.

New Zealand

In February 2010, Medsafe announced Paradex and Capadex were being withdrawn from the marketplace due to health issues, and withdrawal in other countries.

India

On June 12, 2013, the Indian government suspended the manufacture, sale, and distribution of the drug under Section 26A of the 1940 Drugs and Cosmetic Act.

Sweden

In Sweden, physicians had long been discouraged by the medical products agency to prescribe dextropropoxyphene due to the risk of respiratory depression and even death when taken with alcohol. Physicians had earlier been recommended to prescribe products with only dextropropoxyphene and not to patients with a history of substance use disorder, depression, or suicidal tendencies. Products with mixed active ingredients were taken off the market and only products with dextropropoxyphene were allowed to be sold. Dextropoxyphene was de facto narcotica labelled.
As of March 2011, all products containing the substance are withdrawn because of safety issues after a European Commission decision.
At the time, people who drank excessive amounts of alcohol and other substances and take combination dextropoxyphene / acetaminophen were discussed as needing to take many combination tablets to reach euphoria, because the amount of dextropropoxyphene per tablet is relatively low. The ingested paracetamol—the other component—may then reach liver toxic levels. In the case of alcoholics, who often already have damaged livers, even a relatively small overdose with paracetamol may produce hepatotoxicity, liver failure, and necrosis. This toxicity with the combination of overdosed dextroproxyphene and paracetamol-induced liver damage can result in death.